Biomimetic Synthesis of Complex Natural Products The goals of the proposed continuing research program are to develop novel synthetic methods and biomimetic approaches to important classes of bioactive agents, as well as to evaluate compounds in strategic biological collaborations. Approaches include catalytic, asymmetric photocycloadditions using chiral trifluoroethanol catalysis guided by excited state computational analysis, syntheses of bioactive natural products using oxidative dearomatization with bis(-oxo)dicopper(III) complexes including efforts towards catalytic asymmetric oxidations, and reductive isomerization of -alkynyl enones to vinyl allenones and subsequent cycloadditions to access vinylallene-derived natural products. The Principal Investigator, Professor John Porco, and his colleagues will use these new methodologies to synthesize bioactive natural products including the antitumor agents aglaiastatin, sorbicillactone A, chloropestolide A, and the antivira agent humulone. In collaborative studies with investigators at Boston University, the National Cancer Institute (NCI), the Novartis Institutes for BioMedical Research, McGill University, and the Whitehead Institute, Porco and his colleagues will assay the biological activity of the produced compounds. This proposed effort is organized into three core projects with the following aims: Develop catalytic asymmetric photocycloadditions of 3-hydroxyflavones and achieve asymmetric syntheses of the aglains foveoglin A and perviridisin B and the rocaglates aglaiastatin and aglaroxin. Complete asymmetric syntheses of (-)-sorbicillactone A, bisvertinolone and isobisvertinol, sorbifuranones A and C, and humulone and variants. Complete asymmetric syntheses of the antitumor natural products iso-A82775C, pestalofones B and C, chloropestolide A, and chloropupukeananin. This work will carry forward a highly productive research program for Professor Porco and his coworkers. Through their continued collaborations with biological researchers to assess bioactive natural products and derivatives, this new project will lead to the translation of such compounds into evaluation in clinical setting.